Repurposing of the Cardiovascular Drug Statin for the Treatment of Cancers: Efficacy of Statin–Dipyridamole Combination Treatment in Melanoma Cell Lines
Nanami Irie,
Kana Mizoguchi,
Tomoko Warita,
Mirai Nakano,
Kasuga Sasaki,
Jiro Tashiro,
Tomohiro Osaki,
Takuro Ishikawa,
Zoltán N. Oltvai,
Katsuhiko Warita
Affiliations
Nanami Irie
Graduate School of Science and Technology, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda 669-1330, Japan
Kana Mizoguchi
Graduate School of Science and Technology, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda 669-1330, Japan
Tomoko Warita
Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda 669-1330, Japan
Mirai Nakano
Department of Veterinary Anatomy, School of Veterinary Medicine, Tottori University, 4-101 Koyama Minami, Tottori 680-8553, Japan
Kasuga Sasaki
Department of Veterinary Anatomy, School of Veterinary Medicine, Tottori University, 4-101 Koyama Minami, Tottori 680-8553, Japan
Jiro Tashiro
Department of Veterinary Anatomy, School of Veterinary Medicine, Tottori University, 4-101 Koyama Minami, Tottori 680-8553, Japan
Tomohiro Osaki
Department of Veterinary Clinical Medicine, School of Veterinary Medicine, Tottori University, 4-101 Koyama Minami, Tottori 680-8553, Japan
Takuro Ishikawa
Department of Anatomy, School of Medicine, Aichi Medical University, 1-1 Yazakokarimata, Nagakute 480-1195, Japan
Zoltán N. Oltvai
Department of Pathology and Laboratory Medicine, University of Rochester, 601 Elmwood Ave, Rochester, NY 14642, USA
Katsuhiko Warita
Department of Veterinary Anatomy, School of Veterinary Medicine, Tottori University, 4-101 Koyama Minami, Tottori 680-8553, Japan
Metastatic melanoma has a very poor prognosis. Statins, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) inhibitors, are cholesterol-lowering agents with a potential for cancer treatment. The inhibition of HMGCR by statins, however, induces feedback, which paradoxically upregulates HMGCR expression via sterol regulatory element-binding protein-2 (SREBP2). Dipyridamole, an antiplatelet agent, is known to inhibit SREBP2 upregulation. We aimed to demonstrate the efficacy of statin–dipyridamole combination treatment in both human and spontaneously occurring canine melanoma cell lines. The half maximal inhibitory concentration (IC50) of atorvastatin showed a 68–92% reduction when combined with dipyridamole, compared with that of atorvastatin alone. In some melanoma cell lines, cell proliferation was suppressed to almost zero by the combination treatment (≥3 μM atorvastatin). Finally, the BRAF inhibitor, vemurafenib, further potentiated the effects of the combined statin–dipyridamole treatment in BRAF V600E mutation-bearing human melanoma cell lines. In conclusion, the inexpensive and frequently prescribed statin–dipyridamole combination therapy may lead to new developments in the treatment of melanoma and may potentiate the effects of vemurafenib for the targeted therapy of BRAF V600E-mutation bearing melanoma patients. The concordance between the data from canine and human melanoma cell lines reinforces this possibility.
